(1) Field of the Invention
This invention relates to a medical material having excellent compatibility with living bodies, especially with blood.
(2) Brief Description of the Prior Art
Collagen is the principal component of connecting tissues of mammals, such as skins, blood vessels, bones, fasciae and teeth. It serves to protect animals from irritation from the outside and to maintain body configurations and, at the same time, it also serves as a supporting stromata for a variety of cells. Collagen accounts for one third of the whole proteins of mammals and is thus available in abundance. It has therefore found commercial utility in various industrial fields such as the leather, sausage casing and gelatin industries. In recent years, it has also come into the limelight as a medical material. Different from artificial medical materials such as synthetic polymers and ceramics, collagen makes inherently up living bodies and, corollary to this, has various characteristic properties.
(a) Due to its proteinaceous nature, it has of course antigenicity. However, its antigenicity is very weak compared with those of other proteins and its principal antigenic determinant is the telopeptido moiety which may be removed by treating collagen with a protease such as pepsin. Thus, its antigenicity can be reduced by such a pepsin treatment to such an extent that no substantial problem would occur. Its antigenicity may be reduced further by subjecting it to tanning (crosslinking) treatment using glutaraldehyde or the like. PA0 (b) When implanted in a body, collagen is gradually allowed to substitute for a part of the connecting tissue and, as a result, absorbed in the connecting tissue. Thereafter, it is excreted as amino acids and peptides in urine. Since this absorption speed may be lowered by the tanning (crosslinking) treatment, it is possible to control the absorption speed by controlling the tanning treatment. PA0 (c) Owing to its excellent performance as a foot step for the growth of cells, collagen has an effect to expedite the curing of a wounded part when applied thereto. It enjoys excellent compatibility with tissues in living bodies. PA0 (d) When collagen is brought into contact with blood, it induces a platelet agglutination and subsequently development of thrombus. Therefore, it may be used as a medical material for the purpose of obtaining a hemostatic effect. PA0 (e) Since collagen purified from bones has an activity of inducing and promoting osteogenesis, it is also used as an osteogenetic medical material for bone deficiency diseases.
As collagen has properties to cooperate with living bodies as described above, it is used as a substituent for many tissues such as bases of artificial skins, artificial blood vessels, artificial bones, hemostatics, artificial valves, patching materials, artificial tympanic membranes, and hybrid artificial organis, and as materials for contact lenses and drug carriers.
When using collagen as a blood vessel material, it is most common to chemically treat an animal blood vessel and then use the thus-treated blood vessel as an artificial blood vessel. However, collagen promotes the platelet agglutination reaction and forms thrombus when brought into contact with blood, leading to frequent occurrence of clotting of artificial blood vessels in the initial periods of implantation. However, when the formation of thrombus has occurred rather little in the initial period, the thrombus layer will be gradually absorbed and, instead, endothelia will come out from the interior of the living body and will eventually cover up the surface of the artificial blood vessel (i.e., conversion into a pseudo- and endomembrane). Once the artificial blood vessel has been covered by such a pseudo- and endomembrane, thrombus will no longer be formed and the artificial blood vessel will serve just like ordinary blood vessels. Accordingly, it is most important for a collagen-containing artificial blood vessel to minimize the development of thrombus in the initial period of implantation and to promote the conversion into a pseudo- and endomembrane.
One of the present inventors, Dr. Teruo Miyata, reported in "Deposition of Platelets and Fibrin on Chemically Modified Collagen Hollow Fiber", Trans. Amer. Soc. Artif. Int. Organs, 22, 261(1976) that the surface of succinylated collagen has anticoagulant property. Namely, hemeral venous blood was passed through a collagen capillary and the surface of the collagen capillary was observed as to adhesion and agglutination of platelets, deposition of fibrin, etc. The above observation indicated that succinylated collagen produced extremely little deposition of fibrin and far more antithrombotic compared with unsuccinylated collagen. However, it was necessary to determine if the effects of the succinylation would also be brought about in vivo as the above investigation was carried out neither in vivo nor in vitro but in-between, namely, ex-vivo.
On the other hand, another one of the present inventors, Dr. Yasuharu Noishiki, proposed a connective tissue tube making use of a "TETORON" net in "Alcohol-Preserved Homo- and Heterologus Connective Tissue Tube for Arterial Prosthesis", Artif. Organs, 2 (suppl.), 152(1977). The above connective tissue tube was formed by inserting the tube subcutaneously in an animal so that a connecting tissue consisting principally of collagen would cover all over the tube. The connective tissue tube was implanted in the thoracic descending aorta of a dog. Even shortly after the implantation (i.e., a few hours later), a thick thrombus layer having a thickness of 20-100 .mu.m and including solid blood components entrapped therein was formed on the connective tissue tube. This thrombus was absorbed little by little and endothelia came out. This appearance of endothelia, however, took place in about 4 weeks after the implantation. Thus, the curing was very slow.